Modulation of Host Programmed Cell Death Pathways by the Intracellular Protozoan Parasite, Toxoplasma gondii — Implications for Maintenance of Chronic Infection and Potential Therapeutic Applications

Abstract

Programmed cell death (PCD) pathways are genetically programmed mechanisms that can trigger the cell to die or commit “cell suicide”. There are three major forms of pro‐ grammed cell death that are now recognized: apoptosis (type I), autophagy (type II) and necrotic cell death or necroptosis (type III). While these cell death processes were once thought to occupy discrete cell states, evidence suggests that apoptosis, autophagy and necrosis are often regulated by similar pathways and share initiator and effector mole‐ cules and some subcellular compartments indicating that crosstalk exists between these three main forms of cell death pathways, resulting in a balanced interplay by which the cell decides its fate. PCD pathways have important roles in many cellular processes such as development and oncogenic transformation, but PCD pathways also play important roles in host defense and elimination of pathogens. Toxoplasma gondii is a microbial patho‐ gen for which programmed cell death pathways are a key part of the host defense. T. gon‐ dii is an obligate intracellular protozoan parasite that infects approximately one-third of the world’s population. In most immunocompetant individuals, the chronic infection is asymptomatic due to an effective immune response that eliminates active parasite repli‐ cation. The parasite has evolved immune evasion strategies that enable it to survive and persist long enough in the host however to establish a chronic infection in which the cyst stage persists within neurons in the brain and skeletal muscle in the periphery. T. gondii has evolved multiple mechanisms to resist killing by apoptotic, autophagic and necrotic cell death pathways, and the parasite’s manipulation of host PCD pathways plays a cru‐ cial role in host–parasite interactions and maintenance of the chronic infection. While most individuals chronically infected with T. gondii are asymptomatic, severe disease can occur in immunocompromised individuals where the infection reactivates from the brain causing severe necrotizing encephalitis, and increasing evidence indicates chronic cere‐ bral toxoplasmosis in some individuals may lead to neuropsychiatric disorders such as schizophrenia and suicidal behavior. This review will focus on the role of PCD pathways in host defense of T. gondii and the parasite manipulation of these PCD pathways. A bet‐ © 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ter understanding of the molecular components underlying the PCD pathways and the parasite manipulation of these pathways may yield new therapeutic targets for treatment of clinical sequelae of cerebral toxoplasmosis.